In recent years, several novel approaches have been developed to overcome tumor cell resistance to conventional therapeutics. Such approaches include genetic manipulations, vaccine development and exploitation of the anti-tumor host immune response. The overall development of tumor cell resistance to therapeutics is, in large part, the result of the ability of tumor cells to develop specific mechanisms to overcome cell death or apoptosis. Therefore, the possibility to interfere selectively in the regulation of the apoptotic signaling pathways may result in either the direct induction of cell death and/or sensitization of the cells to cytotoxic stimuli. A novel approach based on modifying gene products that regulate resistance to apoptosis involves nitric oxide (NO). NO is a ubiquitous molecule with diverse cellular effects that depend on the source, concentration, latency, cell type and phenotype. This review describes the role played by NO in cancer including carcinogenesis, pathogenesis, angiogenesis, chemoprevention and as a novel therapeutic to overcome resistance when used alone or as a sensitizing agent used in combination with other therapeutics.